The overall goal of my research program is to improve the efficacy and reduce the toxicity of drug therapies by identifying the mechanisms that contribute to the interindividual variability in drug response. The main focus of this effort is on the impact of genomic variability, particularly in the cytochrome P450 (CYP) hepatic drug metabolizing enzyme genes. Metabolism of drugs by the CYP enzymes is the primary elimination route for a large portion of clinically used drugs. Gene-drug and drug-drug interactions are a major cause of inefficacy, adverse events, and hospitalizations from drug therapies. Among the most common interactions are the pharmacokinetic interactions, primarily through the CYP enzymes. There is extensive literature on the effects genetic variants in the CYP coding regions, but this only accounts for a small portion of the pharmacokinetic variability; much less is known about variants in the non-coding regions. Results from our past NIGMS funding have demonstrated that miRNAs regulate the CYP genes and that their regulatory functions are altered by genomic variability. Those studies were focused primarily on SNPs in the 3'UTRs in a few CYP genes. Given the success of those focused studies, over the next five years, we plan to expand these efforts to a broader approach to understanding the role of miRNAs in regulating hepatic drug metabolism. We plan to utilize our novel high throughput assays that test the functional impact of genetic variants in a variety of regulatory regions to identify the functional variants that regulate drug metabolism. Using existing biospecimens and pharmacokinetic data from our completed clinical trials, we will determine the associations of the variants with the in vivo human metabolic activity. Genetic variants shown to impact clinical activity will be incorporated into our ongoing pharmacogenomics clinical implementation efforts, demonstrating the complete bench to bedside program. Variable expression of miRNAs also contributes to the interindividual variability in drug metabolism. Our recent results indicate that there are dramatic changes in hepatic miRNA during the development of the human liver, but little is known about the regulatory mechanisms that control those miRNA expression patterns. To elucidate those mechanisms, we will use state of the art technologies to identify the network of regulatory factors that control normal and aberrant hepatic miRNA expression patterns. Together with my network of documented successful collaborations, we are well equipped to undertake these studies; our team has demonstrated expertise in genomics, pharmacology, bioinformatics with a track record of discovering mechanisms and biomarkers and validating them in clinical trials. We expect the results of these studies to improve our ability to accurately predict the efficacy and toxicity of a variety of drugs that are metabolized through the CYP enzymes. In addition, our discoveries of the molecular mechanism that contribute to the variability in hepatic gene function are likely to have applications to a wide variety of genes and diseases.